To identify genetic determinants of human cancer, cancer families and genetic disorders predisposing to neoplasia are studied in an interdisciplinary approach to gain insights into human carcinogenesis. Linkage studies of our largest NF2 families have confirmed that the NF2 gene is located on chromosome 22q. NF2 thus appears to be genetically homogeneous. We have observed marked interfamily differences in the clinical expression of NF2 based on average age at diagnosis and at death. We have described three clinical groups which comprise four families with mild NF2 (bilateral acoustic neuromas), one family with severe NF2 (extensive meningiomatosis of brain and spinal cord) and seven families with moderate NF2 (bilateral acoustic neuromas plus meningiomas). This observation has important implications for individualized counseling about prognosis and the development of schemes for medical surveillance. We confirmed that a second type of lens opacity (cortical wedges) is a frequent and sometimes early feature of the disorder and described combined pigment epithelial and retinal hamartomas in four individuals in one NF2 family. National Health and Nutrition Examination Survey (NHANES I) follow-up data are being used to generate the following breast cancer incidence rates: overall age- adjusted rates in the cohort, rates by risk factor, and rates in persons with no risk factors. Using the same data, an analysis to determine whether the offspring of older mothers have an increased risk of breast cancer is planned for the near future.